NM_000402.4(G6PD):c.221C>G (p.Ala74Gly) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jun 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000699943.24

Allele description [Variation Report for NM_000402.4(G6PD):c.221C>G (p.Ala74Gly)]

NM_000402.4(G6PD):c.221C>G (p.Ala74Gly)

Gene:

G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000402.4(G6PD):c.221C>G (p.Ala74Gly)

Other names:

G6PD, ALA44GLY; G6PD Odisha; G6PD Orissa; p.Ala44Gly

HGVS:

NC_000023.11:g.154536168G>C
NG_009015.2:g.16405C>G
NM_000402.4:c.221C>G
NM_001042351.3:c.131C>G
NM_001360016.2:c.131C>GMANE SELECT
NP_000393.4:p.Ala74Gly
NP_001035810.1:p.Ala44Gly
NP_001346945.1:p.Ala44Gly
NC_000023.10:g.153764383G>C
NM_001042351.1:c.131C>G
NM_001042351.2:c.131C>G
NM_001042351.3:c.131C>G
NM_001360016.2:c.131C>G

Protein change:

A44G; ALA44GLY

Links:

OMIM: 305900.0047; dbSNP: rs78478128

NCBI 1000 Genomes Browser:

rs78478128

Molecular consequence:

NM_000402.4:c.221C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Synonyms:: Hemolytic anemia due to G6PD deficiency; Favism, susceptibility to; Class I glucose-6-phosphate dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0010480; MedGen: C2720289; Orphanet: 466026; OMIM: 300908

Recent activity

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Homo sapiens zinc finger DHHC-type containing 18 (ZDHHC18), mRNA
Homo sapiens zinc finger DHHC-type containing 18 (ZDHHC18), mRNA
gi|295844835|ref|NM_032283.2|

Nucleotide
superoxide dismutase [Nostoc sp. PCC 7524]
superoxide dismutase [Nostoc sp. PCC 7524]
gi|427365873|gnl|jgi|Nos7524_2766|g 48594.1|

Protein
kiaa0319 KIAA0319 [Danio rerio]
kiaa0319 KIAA0319 [Danio rerio]
Gene ID:794624

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828676	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10192449, 17524386, 15315792, 20621077, 22906047, 26829728, 27880809, 8533762, 28492532
SCV001142116	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 27, 2022)	unknown	clinical testing	Citation Link,
SCV001443094	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002025187	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599317	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Pathogenic (Aug 12, 2022)	maternal	curation	PubMed (15) [See all records that cite these PMIDs] 15315792, 20621077, 22906047, 32425388, 27880809, 21507207, 31863082, 18568599, 12497642, 853376, 30077011, 34620237, 22293322, 10916676, 29300386
SCV004046941	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005068209	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 22, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Three major G6PD-deficient polymorphic variants identified among the Mauritian population.

Kotea R, Kaeda JS, Yan SL, Sem Fa N, Beesoon S, Jankee S, Ramasawmy R, Vulliamy T, Bradnock RW, Bautista J, Luzzatto L, Krishnamoorthy R, Mason PJ.

Br J Haematol. 1999 Mar;104(4):849-54.

PubMed [citation]

PMID:: 10192449

Description of a novel missense mutation of glucose-6-phosphate dehydrogenase gene associated with asymptomatic high enzyme deficiency.

Minucci A, Concolino P, Antenucci M, Santonocito C, Ameglio F, Zuppi C, Giardina B, Capoluongo E.

Clin Biochem. 2007 Aug;40(12):856-8. Epub 2007 Apr 20.

PubMed [citation]

PMID:: 17524386

See all PubMed Citations (21)

Details of each submission

From Invitae, SCV000828676.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 44 of the G6PD protein (p.Ala44Gly). This variant is present in population databases (rs78478128, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 10192449, 17524386). It is commonly reported in individuals of South Asian ancestry (PMID: 8533762, 15315792, 20621077, 22906047, 26829728, 27880809). ClinVar contains an entry for this variant (Variation ID: 10406). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 8533762). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001142116.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV001443094.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant in exon 3 of the G6PD gene results in the amino acid substitution from Alanine to Glycine at codon 74 (p.Ala74Gly) with the sequence change of c.221C>G (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The reference base is conserved across the species and in-silico predictions by SIFT and MutationTaster are damaging. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. The G6PD c.221C>G; p.Ala74Gly variant, also referred to as c.131C>G; p.Ala44Gly, commonly known as G6PD Orissa, has been described in literatures as a Class III variant, associated with moderate enzyme deficiency (Arunachalam et al., 2020; PMID: 32425388, Minucci et al., 2010; PMID: 20621077). This variant has previously been reported for glucose-6-phosphate dehydrogenase deficiency and is most frequent in Indian tribal population (Kaeda et al., 1995; PMID:8533762, Sukumar et al., 2004; PMID:15315792, Lin et al., 2016; PMID:26829728, Sarker et al., 2016; PMID:27880809). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995; PMID:8533762).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002025187.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Dunham Lab, University of Washington, SCV002599317.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (15)

Description

Variant found in unrelated hemizygotes with deficiency, some with anemia and jaundice (PP4, PS4_M). In one family, hemiygote and heterozygous mother both have decreased G6PD activity (PP1). Decreased activity in red blood cells (5-33%) (PS3). In GxxGDLA NADP binding site (PM1). Predicted to be damaging by SIFT and MutationTaster, and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004046941.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The missense c.221C>G (p.Ala74Gly) variant in G6PD gene has been reported in heterozygous state in individuals affected with hemolytic anemia. This variant has been reported to be a common cause of the glucose-6-phosphate dehydrogenase in South Asia, although it has also been reported in other populations (Sukumar et al., 2004). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995). This variant is reported with the allele frequency 0.01% in the gnomAD and 0.02% in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic / Uncertain Significance. The amino acid Ala at position 74 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala74Gly in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV005068209.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

A heterozygous missense variation in exon 3 of the G6PD gene that results in the amino acid substitution of Glycine for Alanine at codon 44 was detected. The observed variant c.131C>G (p.Ala44Gly) has a minor allele frequency of 0.03%, 0.01%, 0.02% and 0.003% in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1) and topmed databases, respectively. The insilico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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